Many people suffer from sleep disturbances, which can result in significant consequences to the health of an individual. Sleep-deprived individuals can have significantly impaired daytime cognition and motor performance. One recognized result of such sleep deprivation is an increase in automobile accidents. The National Highway Traffic Safety Administration estimates that 100,000 car crashes a year are linked to sleepy driving. Nanci Hellmich, “Balancing Act,” Tulsa World, Jun. 2, 2000.
Sleep disturbances associated with pain are especially problematic. Individuals suffering from pain-associated sleep disturbances often have great difficulty staying asleep (sleep duration), and hence getting enough rest during the night. Sleep duration is very important to the physical and mental health of the individuals involved. Because so many individuals suffer from pain-associated sleep disturbances, especially shortened sleep duration, there is a need for a medication to treat these conditions. By pain-associated sleep disorders we mean difficulties falling asleep (i.e., longer time until patient falls asleep) and difficulties saying asleep (i.e., waking too early, before a full night sleep), where either or both of these difficulties are present with or exacerbated by bodily pain, including, but not limited to headache, muscle aches and pain, sore throat, sinus pain, menstrual cramps, back pain, toothache, arthritis.
Ibuprofen, a propionic acid derivative nonsteroidal anti-inflammatory drug (NSAID), has been used in the treatment of pain, injury, and illness for its analgesic, antiinflammatory, and antipyretic effects. It is taken for arthritis, sports injuries, soft tissue trauma, dysmenorrhea, migraine headaches, tension headaches, and dental pain, for example. Ibuprofen is one of the most extensively studied and widely used drugs. It has been estimated that ibuprofen has been used to treat over 100 million patients in at least 100 countries throughout the world. Ibuprofen a very widely used drug in the world. The NSAID ibuprofen has the following chemical structure:

About 80% of an oral dose of ibuprofen in humans is absorbed from the GI tract. Following oral administration, peak serum concentrations are reached within 1 or 2 hours, for suspensions and tablets, respectively. The plasma half-life of ibuprofen has reported to be about 2 hours. The recommended nonprescription dose of ibuprofen for adults is 200 mg every 4 to 6 hours while symptoms persist. If the symptoms do not respond to 1 tablet (200 mg), then 2 tablets can be used. However, no more than 6 tablets should be taken in 24 hours unless directed by a physician. Higher levels of ibuprofen can be used for a prescription product, yielding a dose of 600 or 800 mg every 4 to 6 hours.
Ibuprofen has not previously been known to improve sleep. In fact, quite the opposite, ibuprofen has been shown in some studies of patients not suffering from pain to hinder sleep. Murphy et al., “Nonsteroidal Anti-Inflammatory Drugs Affect Normal Sleep Patterns in Humans,”Physiology & Behavior 55:1063-1066 (1994). Ibuprofen has been shown to increase the number of awakenings and percentage of time spent in stage wake, and decrease sleep efficiency. Ibuprofen has also been shown to delay the onset of deeper stages of sleep. Ibuprofen was thought to have this effect by decreasing prostaglandin synthesis, reducing melatonin synthesis, and changing body temperature. Id. Other studies indicate that ibuprofen has no impact on sleep. Gengo, “The Effects of Ibuprofen on Polysomnographic and Subjective Measures of Sleep in Healthy Adults,” J. Clin. Pharmacol. 36:859 (1996).
Diphenhydramine hydrochloride (2-(diphenylmethoxy)-N,N-dimethylethylamine) is an ethanolamine H1 blocking agent. It antagonizes histamine effects on receptor sites. Diphenhydramine has sedative, antiemetic, anticholinergic, anti-motion sickness, antitussive, CNS excitation and CNS depression, and local anesthetic properties as well. Diphenhydramine hydrochloride and diphenhydramine citrate, two common forms, have the following chemical structures:

The drugs in this group are potent and effective H1 blockers that possess significant antimuscarinic activity and have a pronounced tendency to induce sedation. With conventional doses, about half of those who are treated with drugs in this class experience somnolence. Diphenhydramine has been primarily used for its antihistamine properties, but it has also been used for its somnolent effect and for treatment of motion sickness. There have also been some reports of weak analgesic effects.
Diphenhydramine is well absorbed following oral administration. Following oral administration of a single dose of diphenhydramine, the drug appears in plasma within 15 minutes, and peak plasma concentrations are attained within 1.5 to 4 hours. The usual dose of diphenhydramine as a nighttime sleep aid is 50 mg of diphenhydramine hydrochloride, or an equivalent 76 mg diphenhydramine citrate.
Although diphenhydramine is well-known as a nighttime sleep aid, there exists a need for improved medications for the treatment of sleep disturbances, and in particular, pain-associated sleep disturbances.